The aim of this research proposal is to study mechanisms that regulate cardiac natriuretic peptide (NP) synthesis and release in pulmonary hypertensive states. Hypoxic pulmonary hypertension and cor pulmonale are major causes of morbidity and mortality in patients with chronic lung diseases. Evidence is accruing to suggest that atrial natriuretic peptide (ANP) and possibly brain naturetic peptide (BNP) play significant roles in mitigating the development of pulmonary hypertension and right ventricular hypertrophy during chronic hypoxia. Despite these findings, the mechanisms that regulate NP synthesis and release are not well understood. We plan to study two factors that are likely to be involved in stimulating cardiac NP production during chronic hypoxia: myocardial stretch and reduced oxygen tension. Plasma NP levels, cardiac NP content, and cardiac transcription and translation of NPs will be measured in hypoxic and non-hypoxic models of pulmonary hypertension. In addition, the independent effects of hypoxia and myocardial stretch will be studied in primary cell cultures of rat cardiocytes using hypoxic cell culture chambers and a mechanical cell stretcher. Cardiac production of NPs may be an important hormonal feedback mechanism to protect the right heart from the development of cor pulmonale. By better defining how this mechanism is regulated, we hope to further the understanding of the pathophysiology of hypoxic pulmonary hypertension and provide insight into how NPs might be used to treat patients with pulmonary hypertension or chronic lung diseases.